Intermediates in total synthesis of 16-dehydroprogesterone

ABSTRACT

dl-Pregna-4,16-diene-3,20-dione (16-dehydroprogesterone) and dl17-formylandrosta-4,16-diene-3,20-dione are prepared by a series of reactions starting with 1-methylcyclopropyl methyl ketone.

260/397.l, 260/397.3, 260/397.5, 260/410.9 R, 260/456 P, 260/468 P,260/586 H, 260/593 R, 260/611 A, 260/632 B, 260/654 United States Patent91 [111 3,741,987

Johnson June 26, 1973 INTERMEDIATES IN TOTAL SYNTHESIS OF R16-DEHYDROPROGESTERONE [51] Int. Cl C07d 13/04 [75] Inventor: William S.Johnson, Portola valley [58] Field of Search 260/340.7, 340.9, 260/593R, 410.9 Calif.

[73] Assignee: The Board of Trustees of the Leland 5 References CitedStanford Junior University, OTHER PUBLICATIONS Stanford, Callf.Morrison, et al. Organic Chemistry, 2nd Ed., 1966, pp. [221 F11ed= v1970 248-249, 466-467 and 937-938, Allyn and Bacon, 21 Appl. No.: 70,898Bostofl- 1 Related Application Data Primary Examiner-Alex Maze] [63]Continuation-impart of Ser. No. 788,092, Dec. 30, A i tantExaminer-James H. Turnipseed 1968, Pat. No. 3,598,845. d -d B. Gregg[30] Foreign Application Priority Data [57] ABSTRACT I Dec. 23, 1969Canada 070,702 g y p g 52 US. Cl 260/340.9, 260/340.7, 260/397, and

dione are prepared by a series of reactions starting withlmethylcyclopropyl methyl ketone.

6 Claims, No Drawings INTERMEDIATES IN TOTAL SYNTHESIS l6-DEHYDROPROGESTERONE This application is a continuation-in-part ofapplication Ser. No. 788,092, filed Dec. 30, 1968, now US. Pat. No.3,598,845.

This invention relates to a new synthesis of dl-pregna-4,16-diene-3,20-dione (l6-dehydroprogesterone) and dl-l7-formylandrosta-4,16-diene-3,20-dione, and in particular is concernedwith novel intermediates and process steps in said synthesis.

The starting material for the synthesis is the known l-methylcyclopropylmethyl ketone [Julia et al., Bull. Soc. Chim. France, 1381 (1960)]. Thiscompound is treated with a di-lower-alkyl carbonate in the presence of astrong base to give a l-methylcyclopropyl carbo-lower-alkoxymethylketone of the formula wherein R is lower-alkyl having from one to aboutsix carbon atoms. The reaction is carried out under anhydrous conditionsin an inert solvent at a temperature between about 50C. nd 150C. Thestrong base can be any anhydrous strong base commonly used inbasecatalyzed reactions involving a-substitution of a ketone, forexample, an alkali metal hydride, alkali metal lower-alkoxide or alkalimetal amide.

The next step comprises treating in the presence of a strong base acompound of formula I with an alkyl halide of the formula CH=Cl-l(R)Cl-l hal, wherein R is hydrogen or methyl and hal is halogen,preferably chlorine or bromine, to produce a compound of the formula YCH2 wherein R is hydrogen or methyl, Y is C= and Z iscarbo-lower-alkoxy. The reaction is carried out under anhydrousconditions in an inert solvent at a temperature between about 25 and150C. The strong base can be any anhydrous strong base commonly used inbasecatalyzed acetoacetic ester type condensations, for example, analkali metal hydride, alkali metal loweralkoxide or alkali metal amide.

A compound of formula II wherein R is hydrogen or methyl, Y is C=0 and Zis carbo-lower-alkoxy is then subjected to alkaline hydrolysis anddecarboxylation to give a compound of formula 11 wherein R is hydrogenor methyl, Y is C=0 and Z is hydrogen. The hydrolysis anddecarboxylation is carried out by heating the keto ester with an aqueousalkali metal or alkaline earth metal hydroxide.

The resulting compound of formula 11 wherein R is hydrogen or methyl, Yis C==0 and Z is hydrogen is then reduced with lithium aluminum hydrideto give a carbinol of formula II wherein R is hydrogen or methyl, Y isCH(Ol-l) and Z is hydrogen. The reduction reaction is carried out in aninert solvent at room temperature or below.

The carbinol 11 [R is hydrogen or methyl, Y is CH(OH) and Z is hydrogen]is then treated first with phosphorus tribromide and then with anhydrouszinc bromide to yield a compound of the formula I III wherein R ishydrogen or'methyl, and X is bromine. The phosphorus tribromidetreatment is carried out in an inert solvent at a temperature betweenabout 5 0C. and 0C., preferably in the presence of collidine and lithiumbromide. The anhydrous zinc bromide treatment is carried out in an inertsolvent at a temperature between about --50C. and 0C.

The resulting compound of formula 111 wherein R is hydrogen or methyland X is bromine is heated with an anhydrous alkali metallower-alkanoate in an inert solvent to give a compound of formula IIIwherein R is a hydrogen or methyl and X is lower-alkanoyloxy. Thelower-alkanoyloxy group preferably has from two to four carbon atoms,thus including, for example, acetoxy, propionoxy and butyroxy.

The ester III (R is hydrogen or methyl and X is loweralkanolyoxy) isnext converted to the corresponding alcohol III (R is hydrogen or methyland X is hydroxy) by conventional hydrolysis procedures, or by treatingit with lithium aluminum hydride in an inert solvent.

The alcohol 111 (R is hydrogen or methyl and X is hydroxy) is thentreated with p-toluenesulfonyl chloride in pyridine to give thep-toluenesulfonate ester III (R is hydrogen or methyl and X isp-toluenesulfonyloxy) and the latter then treated with the lithium saltof 4- benzyloxy- 1 -butyne to give a compound of the formula wherein Ris hydrogen or methyl. The reaction is carried out in an inert solventunder anhydrous conditions at a temperature between about 30C. and C.

The benzyl ether IV (R is hydrogen or methyl) is then debenzylatedandpartially reduced by heating it with sodium in liquid ammonia to producea triene of the formula um (mi (1111 (1111 (I a (V -R 1 1 1n oi /(:in v(In cm x--cuiouz wherein R is hydrogen or methyl and X is hydroxy.

The hydroxy triene V (R is hydrogen or methyl and X is hydroxy) istreated with p-toluenesulfonyl chloride in pyridine to produce thep-toluenesulfonate ester V (R is hydrogen or methyl and X isptoluenesulfonyloxy) and the latter treated with lithium bromide inacetone to give the bromo triene V (R is hydrogen or methyl and X isbromine).

In the next step the bromo triene V (R is hydrogen or methyl and X isbromine) is treated with a compound of the formula wherein R islower-alkyl of one to about six carbon atoms and n is 2 or 3, in thepresence of a strong base to produce a compound of the formula wherein Ris hydrogen or methyl, Y is and Z is carbo-lower-alkoxy. The reaction iscarried out in an inert solvent under anhydrous conditions at atemperature between about 30C. and 100C. The strong base can be anyanhydrous strong base commonly used in base-catalyzed acetoacetic estertype condensations, for example, an alkali metal hydride, alkali metallower-alkoxide or alkali metal amide.

The reactant of formula VI is also novel and is prepared by treating themono ethylene glycol or propylene glycol ketal of 2,5-hexanedione with adi-loweralkyl carbonate in the presence of a strong base, for example,sodium hydride.

The keto ester VII (R is hydrogen or methyl, Y is C C H a) n and Z iscarbo-lower-alkoxy) is then subjected to alkaline hydrolysis anddecarboxylation to give the ketone ketal VII (R is hydrogen or methyl, Yis and Z is hydrogen); and the ketal then cleaved by treating it withdilute acid to produce the diketo triene VII (R is hydrogen or methyl, Yis C=0 and Z is hydroen).

g In the next step the diketo triene VII (R is hydrogen or methyl, Y isC=0 and Z is hydrogen) is cyclized by treating it with aqueous basicsolution to give a compound of the formula wherein R is hydrogen ormethyl and Y" is C=0. The aqueous basic solution preferably contains analkali metal hydroxide and the reaction takes place at a temperaturebetween about 50C. and 150C.

The keto tetraene VIII (R is hydrogen or methyl and Y" is C=0) is thentreated with methyllithium or with methylmagnesium halideand thereaction mixture hydrolyzed to give the methyl carbinol VIII [R ishydrogen or methyl and Y" is C(OH)(CH The reaction takes place in aninert solvent at ordinary temperatures.

The methyl carbinol VIII [R is hydrogen or methyl and Y" is C(OH)(CI-Iis cyclized by treating it with a strong acid to give a tetracycliccompound having the formula wherein R is hydrogen or methyl. Thecyclization reaction is preferably carried out at a depressedtemperature (--l0O 0C.), conveniently at the temperature afforded bysolid carbon dioxide (about --C.). The strong acid can be any strongacid appreciably soluble in the solvent at the temperature employed, forexample, a protonic acid such as formic acid, trifluoroacetic acid,fluorosulfonic acid, fluoromethanesulfonic acid, and the like; or aLewis acid such as stannic chloride, boron trifluoride, aluminumchloride, zinc chloride, and the like; and the solvent is preferably anonnucleophilic solvent, for example, methylene dichloride, pentane,1,2-dichlorol ,l ,2,2-tetrafluoroethane, and the like.

The cyclization reaction also produces, along .with

mula

wherein R is hydrogen or methyl. The compound of formula X where R ismethyl can readily be dehydrated with phosphorus oxychloride in pyridineto give the diene IX where R is methyl.

The next step in the synthesis involves cleavage of the tetracyclicdiene IX, wherein R is hydrogen or methyl to the tetracarbonyl compoundhaving the formula wherein R is hydrogen or methyl. The cleavage can becarried out by treating the diene IX with excess osmium tetroxide,followed by cleavage of the bisosmate with hydrogen sulfide to give atetrol, which is treated with excess lead tetraacetate to yield XI.

Alternatively, the tetracyclic diene IX can be cleaved by ozonolysis.The term ozonizing or ozonolysis as used herein includes not only thetreatment of compound IX with ozone but also the decomposition of theintermediate ozonide. The diene IX in an inert solvent is treated withozone, preferably at a depressed temperature (l00 0C.), conveniently atthe temperature afforded by solid carbon dioxide (about -75C.). Theresulting ozonide is not isolated but is decomposed by procedures knownin the art, with reducing agents such as potassium ferro cyanide, sodiumhydrosulfide, sulfur dioxide, zinc and acetic acid, and the like. Theozonide decomposition is carried out at room temperature or slightlyabove, conveniently in the same solvent in which the ozone treatment wasperformed.

The tetracarbonyl compound XI need not be isolated and purified but canbe converted directly to dl-pregna- 4,l6-diene-3,20-dione (XII, R ismethyl) or dl-l7- formylandrosta-4,l6-diene-3,20-dione (XII, R ishydrogen) by treating the tetracarbonyl compound XI (R is methyl orhydrogen) with a cyclization catalyst.

The cyclization catalyst comprises a strong acid (for thin layerchromatographic analysis and gas-liquid phase chromatograpic analysiswith the corresponding spectra and analyses on d-pregna-4,l6-diene-3,20-dione, a known substance derived from naturally occurring steroids (U.S.Pat. No. 2,420,489) and in turn useful in the preparation ofprogestational and cortical hormones.

The dll 7-formylandrosta-4, l 6-diene-3,20-dione (XII, R is hydrogen)can readily be converted by known methods [Woodward et al., J. Am. Chem.Soc. 73, 2404, 3547 (1951); Gash et al. U.S. Pat. No. 2,836,621] todl-l7-carboxy-4-androsten-3-one, the optically active form of which hasbeen converted to desoxycorticosterone (Wilds U.S. Pat. No. 2,5 38,6!1).

The optically inactive dl-forms of the compounds of formula XII can, ifdesired, be resolved into their optically active enantiomers by knownprocedures.

An alternative approach to the synthesis of l6-dehydro-progesteroneinvolves a difference method of conversion of the ketol ester VI to theketo ester VII where R is hydrogen or methyl, Y is C=0 and Z ishydrogen, as follows.

The sodium salt of the keto ester VI is alkylated with l-iodo-3-butyneto give an acetylenic keto ester of the formula:

DB O O C CH C CII (iJI'Ig CH JHQ Hm XIII wherein n is 2 or 3, Y is C=0,and Z is COORKR being lower-alkyl of one to about six carbon atoms.Basic hydrolysis and decarboxylation of the latter gives a keto ketalXIII where Y is C=0 and Z is hydrogen, which is then ketalized to formanacetylenic diketal wherein Y is and Z is hydrogen.

The lithio derivative of the acetylenic diketal (XIII; Y is Z is H) isthen alkylated with a dienic bromide of the formula where R is hydrogenor methyl to afford an acetylenic wherein Y and Y are A is C=C and R ishydrogen or methyl. The latter is selectively reduced with sodium inammonia to give a trienic diketal (XV; Y and Y are C (CHUn A is CH=CHand R is hydrogen or methyl), and acid hydrolysis then cleaves the ketalgroups to give a diketo triene (XV; Y and Y are C=O, A is CH=CH and R ishydrogen or methyl) which is identical with the compound of formula Vllwhere Y is C=O and Z is hydrogen.

The structures of the compounds of the invention, of formulas, l-XV,inclusive, were established by the modes of synthesis, by elementaryanalysis, by interpretation of their ultraviolet, infrared and nuclearmagnetic resonance (nmr) spectra, vapor phase chromatographic analysis(vpc), or by behavior of the compounds in thin layer chromatography(tlc).

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 l-Methylcyclopropyl carbethoxymethyl ketone [1; R is 2 5] A1.85 g. sample of a 54.7 percent dispersion of sodium hydride in mineraloil was washed with three m1. portions of anhydrous pentane undernitrogen. Then 40 ml. of anhydrous diethyl carbonate was added. Thissuspension was stirred while a solution of 2.00 g. ofl-acetyl-l-methylcyclopropane, b.p. l27-l29C. (760 mm.) in 7 ml. ofdiethyl carbonate containing 4 drops of absolute ethanol was added.After the addition was complete, the mixture was stirred for l5 min. at2590, then heated on the steam bath until reaction commenced asindicated by the steady evolution of hydrogen. Gentle heating wascontinued until gas evolution had ceased (about 1 hr.). The mixture wascooled in an ice bath, and a solution of 2.4 ml. of glacial acetic acidin 20 ml. of ether was added. Water was then added, and the aqueousphase was extracted with ether. The combined organic layers were washedwith saturated sodium bicarbonate solution, followed by saturated brine,and dried over anhydrous magnesium sulfate. The residue obtained onevaporation of the solvent at reduced pressure was distilled through a 2ft. spinning band column to remove the excess diethyl carbonate, b.p.3537C. (17 mm.). The yellow oily residue was used without purificationin the alkylation reaction described below.

A sample of the crude keto ester from another run was purified bychromatography on acid-washed alumina. The fraction eluted with 20percent ether in pentane was submitted to short-path distillation atll8-1l9C. mm.) to give l-methylcyclopropyl carbethoxymethyl ketone as acolorless liquid, n 1.4522.

Anal. Calcd. for C H O C, 63,51; H, 8.29.

Found: C, 63.2; H, 8.2.

EXAMPLE 2 l-Methylcyclopropyl l-carbethoxy-3-butenyl ketone 8 11; R isH, Y is c=0, z is cooc,H,

A 0.90 g. sample of a 54.7 percent dispersion of sodium hydride inmineral oil was washed with three 5 ml. portions of anhydrous pentaneunder nitrogen; then 20 ml. of anhydrous tetrahydrofuran was added. Thesuspension was cooled to 0C and stirred while a solution of theaforementioned crude l-methylcyclopropyl carbethoxymethyl ketone(Example 1) in 5 ml. of tetrahydrofuran was added over a period of 40min.'The mixture was stirred for 15 min. at 20-25C.; then a solution of2.37 g. of allyl bromide in 10 ml. of tetrahydrofuran was addedgradually over a period of 20 min. Toward the end of the addition awhite precipitate began to form. The mixture-was stirred at 2025C. for10 hr., then heated at reflux for 1 hr., cooled in an ice bath, treatedwith 5 ml. of water, and the aqueous layer was extracted with ether. Thecombined organic layers were washed thoroughly with brine and dried overanhydrous magnesium sulfate. The pale orange residue obtained on removalof the solvent at reduced pressure was employed, without furtherpurification, in the decarboxylation step described below. A sample ofcomparable material from another run was submitted to short-pathdistillation at -80C. (0.10 mm.) to give l-methylcyclopropyll-carbethoxy-3-butenyl ketone as a colorless liquid, n 1.4579.

Anal. Calcd. for .c,,n,,0,; C, 68,54; H, 8.63

Found: C, 68.5; H, 8.65.

EXAMPLE 3 l-Methylcyclopropyl l-carbethoxy-3-methyl-- -3butenyl ketone[11; R is CH;,, Y is C=O, Z is COOC H The procedure (Example 2)described for the alkylation of l-methylcyclopropyl carbethoxymethylketone was modified. The crude keto ester obtained from 2.03 g. ofl-methylcyclopropyl methyl ketone as described above (Example 1) wasconverted to the sodium enolate with sodium hydride prepared from 0.92g. of the 54.7 percent dispersion. A total of 30 ml. of tetrahydrofuranwas used, and after the addition (30 min.) the solution was stirred for3 hr. at 25C. A solution of 2 g. of methallyl chloride in 5 ml. oftetrahydrofuran was added, and the mixture was heated at reflux for 35hr. At the end of this period a precipitate had formed but the solutionwas still basic. Therefore, 0.4 g. of anhydrous sodium iodide was addedand refluxing continued for an additional 6 hr. The mixture was cooled,water was added, and the aqueous layer was extracted with ether. Thecombined organic solutions were washed well with brine and dried overanhydrous magnesium sulfate. The pale orange liquid residue obtained onevaporation of the solvent under reduced pressure was used in the nextstage of the synthesis without purification. A sample of comparablematerial from another run was chromatographed on acid-washed alumina.The fraction eluted with pentane to 1 percent ether in pentane wassubmitted to short-path distillation at -85C. (0.1 mm.) to givel-methylcyclopropyl l-carbethoxy-3-methyl-3-butenyl ketone as acolorless liquid, n 1.4604.

Anal. Calcd. for C H O C, 69.61; H, 8.99.

Found: C, 69.85; H, 8.9.

in a subsequent larger-scale preparation it was found, that when thestep involving the alkylation of the B-keto ester was carried out byheating at reflux for a total of 65 hr., the reaction was complete andthe addition of sodium iodide was not necessary.

EXAMPLE 4 I with 100 ml. of ether, and the aqueous layer was ex tractedwith ether. The organic layers were combined and washed with water,saturated sodium bicarbonate solution, followed by saturated brine, andfinally dried over anhydrous magnesium sulfate. The oily residueobtained on evaporation of the solvent at reduced pressure was submittedto short-path distillation at 80-90C. (18 mm.) to give 2.43 g. ofl-methylcyclopropyl 3-butenyl ketone as a colorless liquid, n 1.4543.

Anal. Calcd. for C H O: C, 78.21; H, 10.21.

Found: C, 78.4; H, 10.3.

EXAMPLE l-Methylcyclopropyl 3-methyl-3-butenyl ketone [11; R is CH Y isC=0, Z is H] The crude keto ester of Example 3 was saponified anddecarboxylated according to the procedure described above (Example 4)for the lower homolog. Short-path distillation of the product atl05-110C. 17 mm.) gave 2.78 g. of l-methylcyclopropyl 3-methyl-3-butenylketone as a colorless liquid, n 1.4604.

Anal. Calcd. for C H O: C, 78.89; H, 10.59.

Found: C, 79.0; H, 10.5.

EXAMPLE 6 1-Methylcyclopropyl-3-butenylcarbinol [11; R is H, Y isCH(OH), Z is A solution of 0.276 g. of l-methylcyclopropyl 3- butenylketone (Example 4), n 1.4543, in 5 ml. of anhydrous ether was added overa period of 20 min. to a stirred mixture of 0.076 g. of lithium aluminumhydride and ml. of ether. The temperature of the reaction mixture wasmaintained at 0C. during the addition and for another hour afterwards.Saturated sodium sulfate solution (0.25 ml.) was added, and the mixturewas stirred for 15 min. at 1520C. This mixture was allowed to stand overanhydrous sodium sulfate for 30 min., filtered, and the solvent wasremoved under reduced pressure to give 0.270 g. of colorless liquid,which was suitable for use in subsequent steps.

A sample of the crude carbinol prepared as described above from 1.9 g.of ketone was submitted to shortpath distillation at ll0l20C. (18mm.) togive 1.86 g. (96 percent yield) of l-methylcyclopropyl-3-butenylcarbinol as a colorless liquid, n 1.4552.

Anal. Calcd. for C H O: C, 77.09; H, 11.50.

Found: C, 77.25; H, 11.5.

EXAMPLE 7 1-Methylcyclopropyl-3-methyl-3-butenylcarbinol [11; R is CH Yis CH(OH), Z is H] A 2.59 g. specimen of the distilled 1-methylcyclopropyl-3-methy1-3-butenyl ketone described in Example 5, n1,4604, was reduced with lithium aluminum hydride according to theprocedure described above in Example 6 for the lower homolog. Short-pathdistillation of the product at -120C. (17 mm.) afforded 2.54 g. (97percent yield) of lmethylcyclopropyl-3-methyl-3-butenylcarbinol as acolorless liquid, n 1.4606.

Anal. Calcd. for C H O: C, 77.86; H, 11.76. Found: C, 77.8; H, 11.75.

EXAMPLE 8 trans-1-Bromo 3-meth ylocta-3,7-diene [111; R is H, X is Br] Amixture of 2.66 g. of l-methylcyclopropyl-3- butenyl-carbinol (Example6), 1.85 g. of anhydrous collidine, and 3.32 g. of anhydrous lithiumbromide in 40 ml. of anhydrous ether was cooled to -40C. and vigorouslystirred while 1.20 ml. of phosphorus tribromide was added over a periodof a few min. The mixture was allowed to warm to 0C., stirring wascontinued for 1.5 hr., and 2 ml. of collidine was then added, followedby water to destroy the excess )hosphorus tri bromide. The resultingmixture was poured into water overlaid with pentane, and the aqueouslayer was extracted with pentane. The combined organic solutions werewashed with water, saturated sodium bicarbonate solution, and brine, andwere finally dried over anhydrous magnesium sulfate. The residue (3.2g.) obtained on evaporation of the solvent at reduced pressure was addedslowly with stirring to a cooled (40C.) suspension of 3 .75 g. ofanhydrous zinc bromide in 7 ml. of anhydrous ether. A total of 2.4 ml.of ether was used to aid in the transfer. The reaction mixture was thenallowed to warm to 0C., stirring was continued for 1.5 hr., then pentaneand 50 percent saturated brine were added. The aqueous layer wasextracted with pentane,

and the combined organic layers were washed with brine and dried overanhydrous magnesium sulfate. The pale yellow liquid residue (3 g.)obtained on evaporation of the solvent at reduced pressure was washedthrough g. of acid-washed alumina with 500 ml. of pentane to give 2.77g. of trans-1-bromo-3-methylocta- 3,7-diene as a colorless liquid, n1.4870. This product was used in subsequent tranformations withoutfurther purification.

Anal. Calcd. for C H Br: C,

Found: C, 53.6; H, 7.3; Br, 39.1.

The high degree of stereoisomeric purity of this material was indicatedby the nmr spectrum which showed absorption for 3 protons as a singletas 8 1.64 ppm (CH trans C=C), 4 protons as a triplet (J 3cps) ceriteredat 2.10 (C-5 and -6 methylenes), 2 protons as a triplet (.1 7 cps)centered at 2.51 (C-2 methylene), 2 protons as a triplet (J 7 cps)centered at 3.37 (C-l methylene), 3 protons as a set of broad multipletsat 4.75-5.42 (04 and 8 vinylprotons), and 1 proton as 53.20; H, 7.45;Br,

- a multiplet at 5.4-6.1 (C-7 H).

1 1 collidine and 0.5 ml. of water, and the product was isolated asdescribed above to give 0.394 g. of a colorless liquid.

A 0.106 g. sample of the latter liquid was treated with a suspension of0.124 g. of anhydrous zinc bromide in 0.3 ml. of ether as describedabove (Example 8) for the lower homolog. The crude product amounted to0.101 g. of trans-l-bromo-3,7-dimethylocta-3,7-diene as a colorlessliquid. The nmr spectrum at 100 Me showed absorption for 3 protons as asinglet at 8 1.65 ppm (Cl-l at C-3), 3 protons as a singlet at 1.71(Cl-l at C-7), 4 protons as a sharp multiplet centered at 2.01 (C-5 and-6 methylenes), 2 protons as a triplet (J 7.0 cps) centered at 2.50 (OZmethylene), 2 protons as a triplet (J 7.0 cps) centered at 3.37 (CImethylene), 2 protons as a broad singlet at 4.68 (C-8 methylene), and lproton as a broad triplet (J 6.0 cps) centered at 5.25 (C-4 H).

In a larger scale preparation, a 22.2 g. specimen of the carbinol ofExample 7 gave, upon treatment wtih phosphorus tribromide, 28.5 g. (91percent yield) of bromide mixture. An 11.6 g. sample of this bromidemixture, upon treatment with zinc bromide in ether, gave 10.8 g. (93%yield) of trans-1-bromo-3,7-dimethylocta-3,7-diene.

The crude bromide tends to decompose on standing. When purified asfollows, it is considerably more stable. A portion of the crude bromidewas dissolved in pentane and filtered through a column of acid-washedalumina. The yellow oily residue obtained on evaporation of the filtratewas submitted to vapor phase chromatographic analysis. The main fractionwas submitted to short-path distillation at 3540C. (0.05 mm.) to givetrans-l-bromo-3,7-dimethylocta-3,7-diene as a colorless liquid, n1.4940.

Anal. Calcd. for C H Br: C, 55.32; H, 7.88; Br,

36.80. Found: C, 55.5; H, 7.85; Br, 36.6.

EXAMPLE 10 trans-3-Methylocta-3,7-dien-l-ol [111; R is H, X is OH] Amixture of 1.18 g. of the trans-l-bromo-3- methylocta-3,7-diene (Example8) and 2.3 g. of anhydrous potassium acetate in 30 ml. of anhydrousdimethylformamide was stirred under nitrogen at 100C. for 22 hr. Themixture was cooled, water and pentane were added, and the aqueous layerwas extracted with pentane. The combined organic layers were washed withwater followed by saturated brine, and dried over anhy-- drous sodiumsulfate. Most of the solvent was removed by distillation through a 15in. Podbielni'ak-type column. The residue containingtrans-3-methylocta-3,7- dien-l-ol acetate [111; R is H, X is OCOCH wasdiluted with -10 ml. of anhydrous ether, and 0.27 g. of lithium aluminumhydride was then added. The mixture was heated at reflux for 30 min.,cooled to 25C., treated with 0.27 ml. of water followed by 0.27 ml. of15 percent sodium hydroxide, then with an additional 0.8 ml. of .water.The resulting mixture was stirred for 10 min., dried over anhydrousmagnesium sulfate, and filtered. The residue obtained on evaporation ofthe solvent from the combined filtrate and washings amounted to 0.71 g.of a colorless liquid, which was chromatographed on 35 g. of acid-washedalumina. The fraction eluted with 50 percent ether in pentane wassubmitted to short-path distillation at 125C. (26 mm.) to give 0.555 g.(68 percent yield) of trans-3- EXAMPLE 1 ltrans-3,7-Dimethylocta-3,7-dienol [111; R is CH X is 01-1] A solution of0.705 g. of trans-1-bromo-3,7-dimethyl-octa-3,7-diene (Example 9) in16.6 ml. of dimethylformamide was treated with 1.33 g. of potassiumacetate just as described above (Example 10) for the lower homolog. Thecrude acetate [111; R is CH X is OCOCH which amounted to 0.576 g. ofpale yellow oil, was dissolved in 60 ml. of anhydrous methanol, 2.16 g.of anhydrous potassium carbonate was added, and the mixture was stirredfor 1.5 hr. at 25C. Most of the methanol was evaporated under reducedpressure, water wasTdded to the residue, and the mixture was extractedwith ether. The combined organic solutions were washed with waterfollowed by saturated brine and were dried over anhydrous magnesiumsulfate. The crude pale yellow oil obtained on evaporation of thesolvent at reduced pressure was chromatographed on 29 g. of acid-washedalumina. The fraction eluted with 50 percent ether in pentane wassubmitted to shortpath distillation at 122l 23C. (17 mm.) to give 0.334g. of trans-3,7dimethylocta-3,7-dienol as a colorless liquid, n 1.4680.

Anal. Calcd. for C H O: C, 77.86; H, 11.76.

Found: C, 78.0; H, 11.8.

EXAMPLE 12 trans-3 ,7-Dimethylocta3 ,7-dienol p-toluenesulfonate [111; Ris CH X is 4-CH C,H,SO

To a solution of trans-3,7-dimethylocta-3,7-dienol (Example 11) (11.4g., 74.0 mmoles) in 250 ml. of dry pyridine at 0C. under nitrogen wasadded ptoluenesulfonyl chloride (23.8 g., 125 mmoles) in one portion.The solution was degassed withnitrogen and stirred at 05C. for 15 hr.Then 10 ml. of water was added cautiously, followed by ml. of water inone portion. The solution was washed with 3 X ml. portions of ether andthe combined ether solutions were washed with 10 percent aqueous lacticacid until the aqueous layer remained acidic. The organic solution wasthen washed with saturates aqueous sodium bicarbonate solution, driedover anhydrous magnesium sulfate, and concentrated in vacuo to give22.71 g. of trans-3,7-dimethyl-octa-3,7-dienol p-toluenesulfonate as afaintly yellow liquid.

According to the foregoing procedure trans-3- methyl-octa-3,7-dien-l-olcan be interacted with ptoluenesulfonyl chloride to givetrans-3-methylocta- 3,7-dien-l-o1 p-toluene-sulfonate [111; R is H, X is4- CH C' H,SO

EXAMPLE 13 over 1.0 hr. The mixture was stirred at 25C. for 44 hr., then125 ml. of water was added and the aqueous layer was washed with ether.The combined organic layers were washed with saturated aqueous saltsolution, dried over anhydrous magnesium sulfate, and distilled atatmospheric pressure through an 8" Vigreux column to removetetrahydrofuran. The desired 4-benzyloxy-1- butyne was obtained as acolorless oil, b.p. ll7-l l7.5C. (30 mm.), 89.3 g.

b. 1-Benzyloxy-7,l 1-dimethyl-trans-dodeca-3-yne-7,l ldiene [IV; R is CH7 To a flame-dried flask containing 150 ml. of ether and 19.5 g. (0.120mole) of 4-benzyloxy-l-butyne under nitrogen at C. was added a solutionof methyllithium in ether (72.4 ml. of 1.62M solution, 0.117 mole-Addition was complete in min. and the solution was stirred at 24C. for 3hr. Then the ether was removed by distillation at aspirator pressure andreplaced with tetrahydrofuran (freshly distilled from lithium aluminumhydride, 300 ml.). The acetylide dissolved immediately to give a faintlyyellow solution which was transferred to an addition funnel positionedover a mixture of trans-3,7-dimethylocta-3,7-dienol p-toluenesulfonate(Example 12) (22.7 g., 0.0772 moles) in 50 ml. of tetrahydrofuran undernitrogen at 24C. About 200 ml. of the acetylide solution was added andthe mixture was heated at reflux. Additional portions (-35 ml.) ofacetylide solution were added at 20-24 hr; intervals (three times).After 94 hr. at reflux, the solution (heterogeneous) was cooled andpoured into 200 ml. of saturated aqueous sodium chloride solution. Theaqueous solution was washed with 2 X 300 ml. portions of ether; thecombined ether layers were dried over anhydrous magnesium sulfate,filtered, and concentrated at reduced pressure to leave a yellow liquidresidue (ca 40 g.). Rapid column chromatography (200 g. anhydrousmagnesium silicate) gave the desired product, eluted with pentane. Thelatter product was distilled without a fractionating column to afford acolorless liquid, b.p. l50C./3 lb. Final purification via carefulshort-path distillation gave 10.18 g. of l-benzyloxy-7,ll-dimethyl-trans-dodeca-3-yne-7,1l-diene, shown to be 99 percent pure byvpc.

According to the foregoing procedure, trans-3- methyl-octa-3,7-dien-l-o1p -toluenesulfonate can be interacted with 4-benzyloxy-l-butyne in thepresence of methyllithium to givel-benzyloxy-7-methyl-transdodeca-3-yne-7,l1-diene [IV; R is H].

EXAMPLE 14 7,1 l-Dimethyl-trans,trans-dodeca-3,7,1 l-trienol [V; R is CHX is 01-1] A solution of sodium (3.91 g., 0.17 mole) in 380 ml. ofliquid ammonia was prepared under nitrogen. Then a solution of1-benzyloxy-7,11-dimethyl-trans-dodeca- 3-yne-7,11-diene [Example 13,part (b)] (10.0 g., 0.0354 mole) in 100 ml. of anhydrous ether was addedover 15 min. via syringe. After 7 hr., excess ammonium chloride wasadded and the ammonia was allowed to evaporate. The residue salts weredissolved in 100 ml. of water, the ether layer was separated and thewater layer was washed with 2 X 100 ml. portions of ether. After thecombined ether extracts were dried over magnesium sulfate, andconcentrated in vacuo, the yellow, cloudy residue was short-pathdistilled at l20C./3 ,u. to afford 4.912 g. of 7,1l-dirnethyl-trans,trans- I trans,trans-dodeca-3,7,l l-trienol [V; R isH, X is OH].

EXAMPLE 15 7, 1 1-Dimethyl-trans,trans-dodeca-3 ,7, l 1 -trienyl mide[V; R is CH X is Br] p-Toluenesulfonyl chloride (7.62 g., 0.040 mole)was added in one portion to a mixture of7,1l-dimethyltrans,trans-dodeca-3,7,l l-trienol (2.736 g., 13.1 mmoles)in 120 ml. of dry pyridine at 0C. The solution was degassed withnitrogen and allowed to stir at -5C. for 18hr. Then water (ca 10 ml.)was added dropwise over 10 min. with stirring and cooling. More waterml.) was added in one portion and the aqueous layer was washed with 3 X100 ml. portions of ether. The combined ether extracts were washed with10 percent lactic acid until the wash liquid remained acidic and thenwith 10 percent aqueous sodium bicarbonate. The ether solution was driedover anhydrous magnesium sulfate, filtered, and concentrated at reducedpressure to give 8.841 g. of 7,1 l-dimethyl-trans,- trans-dodeca-3,7,ll-trienol p-toluenesulfonate (V; R is CH X is 4-CH C H SO as a faintlyyellow liquid, which could be purified by chromatography on activatedmagnesium silicate and eluting with ether.

Lithium bromide (anhydrous, 13.5 g., 0.155 mole) was dried at 100C./0.05mm. for 6 hr., then added in one portion to a solution of 7,11-dimethyl-trans,transdodeca-3,7,1l -trienol p-toluenesulfonate (4.201g., l 1.6 mmoles) in 1 10 ml. of acetone. The homogeneous mixture wasdegassed'with nitrogen, and stirred. at 24C. for 18 hr. while protectedfrom light with aluminum foil. The acetone was removed by distillationat reduced pressure and the residue was partitioned between 100 ml. ofwater and 100 ml. of ether. The water layer was washed with ether andthe combined ether solutions were dried over magnesium sulfate,filtered, and concentrated in vacuo to give 3.352 g. of 7,11-dimethyl-trans,trans-dodeca-3,7,l l-t-rienyl bromide as a faintly yellowliquid.

According to the foregoing procedure, 7-methyltrans,trans-dodeca-3,7,1l-trienol can be converted to its p-toluenesulfonate ester [V; R is H, Xis 4- Cl-l C H SO and the latter interacted with lithium bromide to give7-inethyl-trans,trans-dodeca-3,7,11- trienyl bromide [V; R is H, X isBr].

EXAMPLE 16 a. 2,2-Ethylenedioxy-5-hexanone I A mixture of2,5-hexanedione (37.0 g.), ethylene glycol (21.0 g.), p-toluenesulfonicacid monohydrate (0.165 g.) and 40 ml. of benzene washeated under refluxfor 2 hr. with a Dean-Stark trap employed to colbrolect the water thatformed (7 ml.). The mixture was cooled to 25C., and was stirred with10ml. of'methanol and 25 ml. of 10 percent potassium hydroxide for 1 hr.The aqueous layer was separatedand extracted with benzene, and thecombined organic layers were washed with water, dried over anhydrouspotassium carbonate, and concentrated at reduced pressure. The

15 residue was repeatedly fractionated by spinning-band distillationwith a center cut of b.p. 105108C. (31 mm.) being retained, to give 15.2g. of 2,2-ethylenedioxy-5-hexanone, n 1.4390.

Anal. Calcd. for C H O C, 60.73; H, 8.92.

Found: C, 60.6; H, 8.8.

By replacing the ethylene glycol in the foregoing preparation bypropylene glycol there can be obtained 2,2-propylenedioxy-5-hexanone.

b. Ethyl 6,6-ethylenedioxy-3-oxoheptanoate [VI; R is C 11 n is 2] Sodiumhydride (16.63 g. of a 52 percent dispersion in mineral oil, 0.371 mole)was washed under nitrogen with pentane and then suspended in 45 ml. ofether. Diethyl carbonate (44.81 g., 0.378 mole) was added, and themixture was warmed in an oil bath at 50C. The2,2-ethylenedioxy-5-hexanone (27.23 g., 0.172 mole) from part (a) abovein 45 ml. of ether was then added dropwise over 1.33 hr. After 20 mliofether was added, the stirring and heating were continued for anadditional 2.5 hr., followed by 13 hr. at room temperature, and another4.5 hr. at 50C. To the cooled (C.) mixture were then added 100 ml. ofether and a solution of 20 ml. of acetic acid in 80 ml. of water. Theexcess acetic acid was quickly neutralized with aqueous sodiumbicarbonate, and the aqueous layer was separated and washed with ether.The ether extracts were combined and washed with successive portions ofsodium bicarbonate solution and water, dried over magnesium sulfate, andconcentrated at reduced pressure to give 39.5 g. of residue consistingof an almost equimolar mixture of ethyl6,6-ethylenedioxy-3-oxoheptanoate and an isomer, ethyl2-acetyl-4,4-ethylenedioxypentanoate. Repeated column chromatography(three times on 400 g. of activated magnesium silicate each time)partially separated the isomers. Ethyl 2-acetyl-4,4-ethylenedioxypentanoate was eluted first with 20 percent pentane inether followed by a mixture of the isomers, and finally pure ethyl6,6-ethylenedioxy-3- oxoheptanoate was eluted by the same solvent. Inthis way 12.7 g. (40 percent yield) of pure ethyl 6,6-ethylenedioxy-3-oxoheptanoate was obtained, n 1.4513.

Anal. Calcd. for C H O C, 57.35; H, 7.88.

Found: C, 57.3;1-1, 7.8.

By an analogous procedure, 2,2-propylenedioxy-5- hexanone can beinteracted with diethyl carbonate to give ethyl6,6-propylenedioxy-3-oxoheptanoate [VI; R 18 C2H5, n 1S 3]- EXAMPLE 176-Carbethoxyl 3, 1 7-dimethy1-2,Z-ethylenedioxy-S-oxo-trans,trans-octadeca-9,13,17-triene [V11; R is CH Y is Z is COOC HSodium hydride (1.244 g. of a 52 percent dispersion in mineral oil,0.0264 mole) was washed under nitrogen with pentane to remove themineraloil, and then dried in a stream of dry nitrogen. A mixture of N,N-dimethylformamide and benzene (4:1, 90 ml.) was added, and thesuspension was stirred at 0-5C. under nitrogen. Ethyl6,6-ethylenedioxy-3-oxoheptanoate (Example 16b) (6.076 g., 0.0264 mole)was added over 15 min. via syringe, and the syringe was rinsed with 5ml. of the solvent mixture. The mixture was kept 20 min. at 05C., andthen 7,1 1-dimethyl-trans,transdodeca-3,7,11-trienyl bromide (Example15) (2.489 g., 0.0918 mole) was added over 15 min. The mixture wasstirred for 15 min. at 25C., and then warmed in an oil bath at 51C. for22 hr. Ether was then added, the mixture was cooled to 20C. and asolution of 3 ml. of acetic acid in 10 ml. of water was added at 10C.After the mixture was stirred for a few seconds, the excess acid wasimmediately neutralized with sodium bicarbonate solution. The aqueouslayer was separated, washed with ether, and the combined ether layerswere washed with successive portions of sodium bicarbonate solution andwater. The solution was dried over magnesium sulfate, and distilled invacuo to give 8.1485 g. of residue. Column chromatography with 500 ofaoti vated magnesium silicate and 30 percent ether in pentane as eluantgave 2.8177 g. (73 percent yield) of 6- carbethoxyl 3,17-dimethy1-2,2-ethylenedioxy-5-ketotrans,trans-octadeca-9,13,17-triene,n 1.4793. Elution with ether afforded 3.504 g. of unreacted keto ester.

Anal. Calcd. for C l-1 0 C, 71.40; H, 9.59.

Found: C, 71.7; H, 9.6.

According to the foregoing procedure, ethyl 6,6-ethylenedioxy-3-oxoheptanoate can be interacted with7-methyl-trans,trans-dodeca-3,7,1 l-trienyl bromide in the presence ofsodium hydride to give 6-carbethoxy-13-methyl-2,2-ethylenedioxy-5-keto-trans,transoctadeca-9,13,17-triene[VI1; R is H, Y is Z is COOC H EXAMPLE l813,17-Dimethyl-2,2-ethylenedioxy-5-oxo-trans,transoctadeca-9,l3,l7-triene[VI1; R is CH Y is (3 (CHM,

Z is H] 6-Carbethoxy-1 3 ,1 7-dimethyl-2,2-ethylenedioxy-5-oxo-trans,trans-octadeca-9,1 3 l 7-triene (Example 17) (2.702 g.) wasdissolved in 4.2 ml. of ethanol; 5.65 g of barium hydroxide octahydrateand 15.4 ml. of water were added. The mixture was degassed and stirredunder nitrogen in an oil bath at l 15C. for 16 hr. With the solution at0C., ether was added, followed by a solution of 4 ml. of hydrochloricacid in 36 ml. of water. The excess acid was immediately neutralized andthe solution filtered. The aqueous layer was separated and washed withether. The ether extracts were combined and washed with successiveportions of sodium bicarbonate solution and water, and then dried overmagnesium sulfate. The solvent was removed by rotary evaporation toleave 1.8849 g. of residue which was chromatographed on 70 g. ofactivated magnesium silicate (10 percent ether in pentane as eluant), togive 1.3981 g. of 13, l 7-dimethyl-2,Z-ethylenedioxy-S-oxo-trans,-trans-octadeca-9,13 ,17-triene, n 1,4798.

Anal. Calcd. for C H O C, 75.82, H, 10.42.

Found: C, 75.8; H, 10.4. According to the foregoing procedures,6carbethoxy- Z is H], orl3,17-dimethyl-2,2-propylenedioxy--oxotrans,trans-octadeca-9,13,17-triene[VII; R is CH Y is C ECHM,

Z is H], respectively.

EXAMPLE 19 13 ,17-Dimethyl-2,5-dioxo-trans,trans-octadca- 9,13,17-triene[VII; R is CH Y is C=O, Z is H] A solution ofl3,17-dimethyl-2,2-ethylenedioxy-5- oxo-trans,trans-octadeca9,13,17-triene (Example 18) (0.3091 g.) and 15 ml. of 0.1N hydrochloricacid in 60 4 ml. of methanol was stirred under nitrogen for 1 hr. at

30-33C. and for 3 hr. at 3334.5C. The acid was neutralized by additionof excess solid calcium carbonate, the solid was filtered, and themethanol was distilled at aspirator pressure. The residue was repeatedlyextracted with ether, and the extracts were washed with successiveportions of sodium bicarbonate solution and water. The solution wasdried over anhydrous magnesium sulfate, and the solvent was removed atreduced pressure to give a yellow liquid, 0.2727 g., which was distilledto give 13,17-dimethyl-2,5-dioxo-trans,transoctadeca-9,13,17-triene, n1.4779.

Anal. Calcd. for C H O C, 78.89; H, 10.60.

Found: C, 78.83; H, 10.53.

According to the foregoing procedure, l3-methyl 2,-2-ethylenedioxy-5-oxo-trans,trans-octadeca-9,13,1 7- triene can betreated with methanolic hydrochloric acid to give13-methyl-2,51dioxo-trans,trans-octadeca- 9,13,17-triene [VII; R is H, Yis C=O, Z is H].

Alternatively, l3 l7-dimethyl-2,5-dioxo-trans,transoctadeca-9,13,17-triene can be preparedby treating 6- carbethoxy-13 l7-dimethyl-2,2-ethylenedioxy-5-oxotrans,transoctadeca-9,13,17-triene(Example 17) with hydrochloric acid in methanol according to theprocedure of Example 19 to cleave the ketal and obtain 6- carbethoxy-3,17-dimethyl-2,5-dioxo-trans,transoctadeca-9,13,l7-triene [VII; R is CHY is C=O, Z is COOC H and the latter hydrolyzed with barium hydroxideaccording to the procedure of Example 18.

6-carbethoxyl 3, l 7- EXAMPLE 20 2-( 7,1 1rDimethylstrans,trans-dodeca-3,7 ,1 1-trienyl)- 3-methyl-cyc1opent-2-en-l-one [VIII; R is CH;,, Y" isC=O] l3 ,17-Dimethyl-2,5-dioxo-trans,trans-octadeca- 9,l3,l7-triene(Example 19) (0.1290 g.) in 15 ml. of 2 percent sodium hydroxide and 5ml. of ethanol was stirred under nitrogen at 105-110C. for 6 hr., then Ineutralized with 0.5N hydrochloric acid and extracted with ether. Theether solution was washed with successive portions of sodium bicarbonatesolution and water, dried over magnesium sulfate, and concentrated atreduced pressure to give 0.1218 g. of product. The combined productsfrom two such reactions were purified by preparative thick layerchromatography (CF- silica gel) and developed for 1.5 hr. with 25percent ether in pentane as eluant. The fastest moving uv-activecomponent was collected by ether washing and shown to be 2-( 7 ,1l-dimethyl-trans,trans-dodeca-3,7,l l-trienyl)-3-methylcyclopent-2-en-l-one by ir, uv, and nmr spectroscopy, obtained in84 percent yield.

Anal. Calcd. or C I-1 0: C, 83.88; H, 10.56.

Found: C, 83.16; H, 10.66. 7

According to the foregoing procedure, 13methyl-2,5-dioxo-trans,trans-octadeca-9,13 l 7-triene can be treated with dilutesolium hydroxide to give 2-( 7- methyl-trans,trans-dodeca-3 ,7,1l-trienyl)-3- I methylcyclopent-2-en-l-one [VIII; R is H, Y is C=O].

EXAMPLE 21 2-( 7 ,l 1-Dimethyl-trans,trans-dodeca-3 ,7,1 l-trienyl)-l,3-dimethylcyclopent-2-en-l-ol (VIII; R is CH;,, Y" is X M To asolution of 2-(7,1 1-dimethyl-trans,transdodeca-3 ,7,ll-trienyl)-3-methy1cyclopent-2-en-1-one (Example 20) (206 mg., 0.721mmole) in ml. of anhydrous ether at 24C. under nitrogen was added asolution of methyllithium in ether (prepared from lithium and methyliodide, 2.0 ml. of 1.5M solution, 3.0 mmoles). The mixture was kept for30 min. at 24C. Water (0.054 ml., 3.0 mmoles) was added in one portionvia syringe and the solution was stirred for 10 min.

to decompose the excess methyllithium. Then another 4 portion ofmethyllithium (2.0 ml., 3.0 mmoles) was added and allowed to react for30 min. at 24C. The mixture was then poured into 20 m1. of cold waterand diluted with 10 ml. of ether. The organic layer was separated,washed with 20 ml. of saturated aqueous salt solution, dried overanhydrous magnesium sulfate, and concentrated by rotary evaporation toafford 217 mg. of 2-( 7,1 l-dimethyl-trans,trans-dodeca-3,7,1ltrienyl)-1,3-dimethylcyclopent-2-en-l-ol as a slightly yellow liquid,217 mg.; infrared spectrum: 3700-3400 w (OH), 1710 vw (C=C), 1600 m(C=C), 974 s (trans-HD=CH), 894 cm s (C=CH According to the followingprocedure, 2-(7-methyl- ,trans,trans-dodeca-3 ,7,ll-trienyl-3-methylcyclopent- 2-en- 1 -one can be treated withmethyllithium to give 2- (7-methyl-trans,trans-dodeca-3 ,7,l1'-trieny1-l,3- dimethylcyclopent-Z-en-l-ol [VIlI; R is H, Y" is X QLEXAMPLE 22 dl-3 ,17-Dimethyl-A-nor-D-homoandrosta-3 ,16-diene [IX; R isCH 2-(7,l 1-Dimethyl-trans,trans-dodeca-3,7,l l-

19 trienyl)-l ,3-dimethylcyclopent-2-en-1-ol (Example 21 (217 mg., 0.721mmole) was dissolved in dichloromethane (freshly dried), flushed withnitrogen by alternately evacuating and filling, cooled to 78C. (solidcarbon dioxide-acetone bath), and stirred with a magnetic stirring bar.Then anhydrous trifluoroacetic acid (distilled from phosphoruspentoxide, sotred in a desiccator containing calcium chloride, 5.0 ml.)was added dropwise over three min. via syringe. A larger portion of theacid appeared in solid suspension and an oragne color developed withinminutes. This mixture was kept 24.5 hr. aat 78C., and then poured into alarge beaker containing 100 ml. of saturated aqueous sodium bicarbonatesolution. The mixture was stirred until the ice melted, then the aqueouslayer was separated and washed with dichloromethane (2 X portions). Thecombined organic layers were dried over anhydrous magnesium sulfate andconcentrated by rotary evaporation to afford a yellow liquid, 231 mg.Thin layer chromatography showed two spots (R, 0.71 and 0.63,

pentane on silica gel) in addition to several unresolved components oflow R, The infrared spectrum of the crude cyclization product (CHClindicated the presence of trifluoroacetate (1730 cm), with small peaksat 970 cm (internal trans double bond) and 890 cm (terminal methylene).

The crude cyclization product was stirred in anhydrous ether ml.) at24C. and solid lithium aluminum hydride (70 mg., 1.84 mmoles, ca tenfoldexcess) was added all at once. After 30 min., successive portions ofwater (70 pl), percent aqueous sodium hydroxide solution (70 .4.1.), andwater (210 pal.) were added cautiously at a rate to avoid excessivebubbling. The mixture was stirred until the suspension was uniformlywhite (ca 10 min.) and then filtered. The residue was washed with ml. ofether and the combined filtrate and wash solutions were concentrated byrotary evaporation to afford a colorless liquid (204 mg.). Infraredspectral analysis (CHCl indicated the absence of trifluoroacetate andthe presence of hydroxyl (3500 cm). Rapid chromatography (2.0 g. ofactivated magnesium silicate) gave 67 mg. of a hydrocarbon fractioneluted with pentane and 140 mg. of an alcohol fraction eluted withether.

The hydrocarbon fraction was distilled (short-path, 120C. bath, 3microns) to afford 52 mg. of colorless, crystalline distillated. Tlcanalysis detected a major component of R, 0.71 (pentane on silica gel)and a trace constitutent at R, 0.63. Vpc analysis (55% SE 30 onchromosorb W, 170C., N carrier gas) gave a minor peak (16.5 min.,relative area 0.04) and a major peak (21.2 min., area 0.96). Preparativetlc gave dl-3,17- dimethyl-A-nor-D-homoandrosta-3,16-diene 99 percentpure by vpc, m.p. 6l-64C., colorless blades from methanol). Nmr spectralanalysis (CCl was entriely consistent with the assigned structure(angular methyls at 0.78 and 0.88 8; vinyl methyl at 1.57 8; vinylhydrogen 1 at 5.33 8). The infrared spectrum (CCl indicated the absenceof terminal methylene absorption (expected at 890 cm).

Anal. Calcd. for C H C, 88.7; H, 11.3.

Found: C, 88.5; H, 11.4.

The alcohol fraction consisting of dl-3,l7-dimethyl-A-nor-D-homoandrost-3-en-l7-ol [X; R is CH was stirred with 0.2 ml. offreshly distilled phosphorus oxychloride in 2.0 ml. of dry pyridine at24C. under nitrogen for 16 hr. Then ether (10 ml.) and water (10 ml.,

58 mg. of a hydrocarbonfractionwhich was iiisTiITJd a? above to producea colorless, crystalline distillate (49 mg.) containing dl-3, 17-dimethyl-A-nor-D-homoandrosta-3,16-diene, purified by tlc separationas above. The over-all yield ofdl-3,17-dimethyl-A-norD-homoandrosta-3,16-diene was 81 mg., 40 percent.

According to the foregoing procedure, 2-(7-methyltrans,trans-dod eca-1,7,l 1-trienyl)- 1 ,3- dimethylcyclopent-Z-en-1-ol can be cyclized withtrifluoroacetic acid to give dl-3-methyl-A-nor-D-homoandrosta-3,16-diene[lX; R is H].

EXAMPLE 23 dl-3 ,17-Dimethyl-A-nor-D-homoandrosta-3 1 6-diene IIX; R isCH 2-( 7 ,1 l-Dimethyl-trans,trans-dodeca-3 ,7,1 1- trienyl )-l,3-dimethylcyclopent-2-en-1-ol (Example 21) (22.1 mg.) was dissolved in18 ml. of dry dichloromethane, flushed with nitrogen, cooled to 78C.with stirring, nd treated with mg. (0.29 mmole) of stan- .nic chloride(in 1 ml. of dry dichloromethane). The resulting yellow solution wasstirred for 1 hr. at -78C. and quenched at this temperature with 200uLof dry pyridine to give a colorless solution which was poured onto 25ml. of cold 1N HCl and 20 ml. of dichloromethane. The aqueous layer wasextracted with two more l5-ml. portions of dichloromethane and thecombined organic extracts were washed with saturated sodium bicarbonatesolution, dried over anhydrous magnesium sulfate and concentrated underreduced presure to give 21.6 mg. of a pale yellow oil. A vpcchromatogram of this material on 5 percent SE 30 column .had a majorpeak (tetracyclic material) representing 83 percent of the total area.This material was chromatographed on 2 g. of activated magnesiumsilicate to give 16.2 mg. of a colorless material which eluted withpentane and 4.1 mg. of a yellow material which eluted with ether. Thepanetane eluant, which partially crystallized upon standing, was furtherpurified by preparative tlc on a 4 X 8 inches plate coated wtih 10 g. ofsilica gel using ether as the solvent. The major fraction was-collectedand extracted with ether to afiord 11.0 mg. of dl-3 ,17-dimethyl-A-nor-D-homoandrosta3 l 6-diene as a white waxy solid, mp59-66C. The nmr spectrum (CDCl solution) exhibited absorptions for theG18 and C-19 angular mehyl groups at 8 0.80 and 0.89, respectively, anda vinyl proton at 8 5.33 consistent with the 16,17 double bond isomer.

In another run, 2-(7,1 l-dimethyl-trans,trans-dodeca- 3,7,1l-trienyl)-1,3-dimethylcyclopent-2-en-l-ol (580 mg.) was dissolved inml. of nitromethane, degassed and flushed with nitrogen several times,cooled in a Dry lee-carbon tetrachloride bath (23C.), and treated viasyringe with 1.78 g. (6.83 mmoles) of stannic chloride in 8 ml. ofdegassed nitromethane over a 3 min. period. The resulting yellow-orangemixture was stirred for 3 hrs. at 23C., then quenched by the addition of1.2 ml. of dry pyridine via syringe at this temperature to give a whitemixture which was pouredonto ml. of cold 1N hydrochloric acid coveredwith 150 ml. of ether.

Theaqueous layer was extracted with four 75 ml. portions of ether andthe combined ether solutions were washed three times with saturatedsodium bicarbonate solution (white suspension in aqueous layer) anddried over anhydrous magnesium sulfate. The solvent was re- EXAMPLE 24 l2( lH)-naphthalenone [Xli R is CH By Osmolation of Tetracyclic Diene.dl-3 ,l7- Dimethyl-A-nor-D-homoandrosta-3 l 6-diene (Example 22) (32.6mg., 0.115 mmole) was dissolved in 2.0 ml. of pyridine (distilled fromcalcium hydride, stored over I barium oxide) and solid osmium tetroxide(63 mg., 0.245 mmole) was added all at once. The mixture (rapidlyturning brown) wasflushed with nitrogen and stirred at 24C. for 48 hr. Abrown solid appeared after about 4 hr. The pyridine was removed byrotary evaporation and the brown powder was dissolved in 2-3 ml. ofdimethyl sulfoxide (distilled from calcium hydride) by warming on asteam bath. Hydrogen sulfide was bubbled into the brown homogeneoussolution for 5.0 min., and the resulting mixture was shaken with 50 ml.of dichloromethane overlaid with 50 ml. of water. The resulting blacksuspension was filtered with suction and the nearly colorless filtrateseparated into two layers. The aqueous layer was washed with three 30ml. portions of dichloromethane, and the black residue was washed with30 ml, of tetrahydrofuran (freshly distilled from lithium aluminumhydride). The combined organic solutions were dried with magnesiumsulfate and concentrated by rotary evaporation, first at aspiratorpressure and finally at oil pump vacuum to remove dimethyl sulfoxide.The residue was a yellow solid, 71

' mg. Trituration with 2-3 ml. of ether gave a nearly colorless solutionfrom which was isolated by evaporation the tetrol derivative, 48 mg.

A sample of crude tetrol derivative (ca 0.1 mole) was dissolved in 2.0ml. of tetrahydrofuran (freshly distilled from lithium aluminum hydride)and stirred at C. Lead tetraacetate (143 mg., 0.34 mmole) was added as asolid in portions over one min. A yellow solid began to formimmediately. After 5 min., 30 ml. of dichloromethane was added andthesolution was washed with ml. of 3 percent aqueous hydrochloric acidfollowed by 10 ml. of 5 percent aqueous potassium carbonate. The organiclayer was dried over magnesium sulfate and concentrated by rotaryevaporation to leave 10-(3-oxobutyl)-5B-formylmethyl-6a-(2oxopropyl)-101,65- dimethyl-3 ,4 ,4afl ,5,6 ,7,8 ,8aa-octahydro 2(l H)- naphthalenone as a yellow oil, 45.7 mg.

According to the foregoing procedure, dl-3-methyl-A-nor-D-homoandrosta-3,16-diene [lX; R is H] can be cleaved byosmolation to give 1a-(3-oxobutyl)-5,8,6adi(formylmethyl)-la,6B-dimethyl-3,4,afl,5,6,7,8,8aaoctahydro-2(lH)-naphthalenone [XI; R is H].

duced EXAMPLE 25 ld-(3 Oxobutyl)-SB-formyIirietHyl-6a-(2 oxopropyl)-1a,6B-dimethyl-3,4,4afl,5 ,6,7 ,8,8aa-octahydro-2( 1H naphthalenone [XI;R is CH I By Ozonolysis of Tetracyclic Diene IX A solution of 12 mg.(0.042 mmole)i of dl-3,17- dimethylA-nor-D-homoandrosta3 ,1 6-diene(Example 2), which had been evaporatively distilled at l20-l25C. (3lm.p. 59-'67C., in 2.0 ml. of dichloromethane and 0.5 ml. of pyridinewas cooled with stirring to -78C. and treated with ozone-oxygen until ablue color developed. The solution was stirred for another 15 min.,treated with 80 mg. of zinc powder and 0.4 ml. of acetic acid, andallowed to warm to 0C. The treatment with zinc and acetic acid wasrepea'tedafter 1-5 min. and the solution was stirred at 0C. for anadditional 45 min. The zinc was removed by filtration affording acolorless filtrate which was diluted with 20 .ml. of dichloromethane andwashed twice with saturated sodium bicarbonate solution and once withsaturated brine. The organic layer was dried with'anhydrous magnesiumsulfate and concentrated under repressure to give 15.5 mg. of la-( 3-oxobutyl )-5fi-formylmethyl-6a-( 2-oxopropyl)- la,6B-dimethyl- 3,4,4aBB,5 ,6,7,8 ,8aa-octahydro- 2( ll-l)-naphthalenone as a pale yellowoil, k 3.67 (Cl-10, w) and 5.87 p. (C=O, s). TLC on silica gel showed amajor spot of R, 0.12 upon development with ether and a faint spot of R,0.33. This material was used immediately in the subsequenttransformation without further purification. I

According to the foregoing procedure, dl-3-methy1-A-nor-D-homoandrosta-3,16-diene [IX; R is H] can be ozonized to givela-(3-oxobutyl)-5B,6adi( formylmethyl l a,6B-dimethyl-3 ,4,4aB',5 ,6,7,8,8aaoctahydro-2(1H)-naphthalenone IXI; R is H].

EXAMPLE 26 dl-Pregna-4,l6-diene-3,20-dione [XII; R is CH5] The solidcrude triketoaldehyde from Example 24 (45.7 mg.) was stirred with 2.5percent aqueous potassium hydroxide under nitrogen at 74C. for 13 hr.The

mixture became yellow with a brown solid. The solution was diluted with10 ml. of 3 percent aqueous hydrochloric acid, and washed with four 10ml. portions of dichloromethane. The combined organic extracts weredried over magnesium sulfate and concentrated by rotary evaporation toleave a yellow solid,.39 mg. Preparative tlc (1:1 pentane:ether, silicagel, continuous evaporation for one hr.) gave 5.0 mg. of dl-pregna-4,l6-diene-3,20-dione (R, ca 0.35) which was estimated to be 80-90percent pure by analytical tlc, and

1 1 mg. of a mixture running slightly slower. The 1 1 mg. mixture wasre-plated as before with continuous evaporation for 3 hr. to provideclean separation of the l6-dehydroprogesterone fraction, 4.2 mg. with 110.45. Total yield of l6-dehydroprogesterone was 9.2 mg., 29 percentoverall from the tetracyclic diene 1X. Vpc analysis (S-ft. X %-in., 5%SE 30 on chromosorb W at 255C., N carrier at 18 psi) gave onepeak at 8.6min., identical .with commercial material. Similarly, the nmr (CDCI andinfrared (Cl-ICl spectral data for synthetic and commercial samples ofl-dehydroprogesterone were identical in every respect. Crystallizationfrom benzene-hexane gave theanalytical sample as prisms, m.p. 182-l86C.The natural material (from benzene-hexane) had m.p. 182-l84C.

Anal. Calcd. for C H O C, 80.73; H, 9.03.

Found: C, 80.54; H, 9.06.

According to the foregoing procedure,la-(3-oxobutyl)-5fi,6a-di(formylmethyl)-101,613- dimethyl-3 ,4,4a,8,5,6,7,8,8aa-octa-hydro-2( 1H)- naphthalenone [XI; R is H] can becyclized withpotassium hydroxide is give 'dl l'7-fofiylafidrosta 4fl6-diene-3,20-dione (X11; R is H].

EXAMPLE 27 dl-Pregna-4,l6-diene-3,20-dione [Xll; R is C11,]

The ozonolysis product 15.5 mg.) from Example 25 was dissolved in 1.2m1. of a solution made from 3.0 ml. of acetic acid, 0.3 ml. ofconcentrated hydrochloric acid, and 0.075 ml. of water, then refluxedunder a nitrogen atmosphere for 2.5 hrs. The reaction mixture wasconcentrated under reduced pressure to give a brown residue which wastakenup in 10 ml. of ether and washed with saturated sodium bicarbonatesolution and brine. The organic solution was drived over anhydrousmagnesium sulfate and concentrated under reducedpressure to give 8.9 mg.of a brown oil. This material was purified by preparative tlc on a 2 X 8inch plate coated with silica gel and the major fraction, developed withether, was collected and extracted with tetrahydrofuran to give 38 mg.of a pale yellow oil which solidified upon standing. This material wasrecrystallized twice from ether and once from benzenehexane to givewhite plates (1.0 mg.) melting at 184-- 187C. This material uponadmixture with the d1- pregna-4,l6-diene-3,20-dione obtained in Example26 (mp. l82 186C.) also melted at 184-187C.

dl-Pregna-4, l 6-diene-3,20-dione anddl-17-formylandrosta-4,l6-diene-3,20-dione can be resolved into theird-and l-forms by conversion to the respective hydrazone derivatives withl-menthylhydrazine, separation of the diastereoisomeric forms, andreconversion EXAMPLE 2s Ethyl 2-(3-butynyl)-6,6-ethylenedioxy-3-oxoheptanoate [XIII; n is 2, Y is C=O, Z is COOC l-l A solution of 75 g.(0.42 mole) of 4-iodo-1-butyne (n 1.5492) in 85 ml. of dry acetonitrilewas degassed and flushed with nitrogen several times then 35.6 g. (0.1415 urnole) of ethyl sodio-6,6-ethylenedioxy-3-oxoheptanoate (Example 17)was added and the resulting yellow solution was again degassed andflushed with nitrogen. The solution was heated at 70C. under nitrogenfor 12 hr., the cooled and poured onto 500 m1. of ice-water and 1250 ml.of ether. The aqueous layer was extracted with ether (3 X 200 ml.) andthe combined ether solutions were washed with brine and dried overanhydrous magnesium sulfate. The organic solution was concentrated firstby atmospheric distillation through a Vigreux column followed by vacuumdistillation through a microdistilling heat to give 25 g. of unchanged4-iodo-1- butyne, b.p. 25-45C. (15 mm.) and 43.5 g. of a pale yellowdistillation residue. The latter material was submitted to high vacuumdistillation through a microdistilling head to give 7.88 g. of acolorless oil, b.p. ll4117C. (0.05 mm.) and a yellow distillationresidue which was evaporatively distilled at ll5-l20C. (5 p.) to give29.1 g. (7 percent yield) of ethyl 2-(3-butynyl)-6,6-ethylenedioxiy-3-oxoheptanoate as a colorless oil, n1.4651.

EXAMPLEQT 9,9-Ethylenedioxy-6-oxo-l-decyne [X11]; n is 2, Y is C=O, Z isH] A mixture of 28.2 g. (0.100 mole) of ethyl 2-(3-butynyl)-6.6-ethylenedioxy-3-oxoheptanoate (Exam ple 28), n 1.4651, ml.of absolute ethanol, and

245 ml. of distilled water was degassed and flushed with nitrogenseveral times. Barium hydroxide octahydrate (88 g., 0.28 mole) was thenadded and the resulting mixture was degassed again and heated undernitrogen for 16 hrs. at -l00C. The reaction mixture was cooled, pouredonto 200 g. of ice covered with 750 ml. of pentane, acidified with 370ml. of 2N hydrochloric acid, swirled for 3 min., and made alkaline bythe addition of sodium bicarbonate solution. The basic aqueous layer wasextracted with pentane (3 X 400 ml.) and the combined organic solutionswere washed with water and brine, then dried over anhydrous magnesiumsulfate. The solvent was removed by atmosphericdistillation through aVigreux column to afford a residue which was evaporatively distilled at90-100C. 5 u) to give 15.26 g. (73 percent yield) of9,9-ethylenedioxy-6- oxo-l-decyne as a colorless oil.

EXAMPLE 30 6,9-bis-Ethylenedioxy-l-decyne [X11]; n is 2, Y is 2' is H] vA mixture of 15.2 g. (72 mmoles) of 9,9- ethylenedioxy-tS-oxo-l-decyne(Example 29), 17.5 ml.

(19.4 g., 312 mmoles) of ethylene glycol, 125 mg.

(0.66 mmole) of p-toluenesulfonic acid monohydrate, and 500 ml. ofbenzene was degassed and flushed with nitrogen several times. Themixture was then boiled underreflux for 16 hrs. while the water wasremoved azeotropically with a Dean-Stark trap. After cooling,

distilled at l00-105C. (5 u) to give 18.5 g. percent yield) of6,9-bis-ethylenedioxy-1-decyne as a colorless oil. v

EXAMPLE 31 a. trans-1-Bromo-3,7-dimethylocta-3,7-diene [)(lV;

R is CH A mixture of 25.1 g. (0.144 mole) ofo-phenylenephosphorochlorodite and 25 ml. of dry pyridine in 330- ml. ofdry ether was cooled to 0C. under nitorgen while 20.0 g. (0.130 mole) of1-methylcyclopropyl-3- methyl-3-butenylcarbinol, n,, 1.4609, in 60 ml.of dry ether was added over a 30 min. period. The white suspension wasstirred 2.5 hrs. at room temperature, then filtered and washed withether. The filtrate and washings were washed wtih cold water, 10 percentv/v lactic acid, saturated sodium bicarbonate solution, and brine, thendried over anhydrous magnesium sulfate. The solvent was removed underreduced pres sure to give 42 g. .of a colorless oil which wasusedimmediately in the subsequent transformation.

A solution of the crude phosphite (42 g.) in 70 ml. of dry ether wasadded over 30 min. to a mixture of 58.5 g. (0.26 mole) of dry zincbromide, 730 mg. of calcium oxide, and 580 m1. of dry ether. Theresulting pale yellow mixture was stirred under nitrogen at roomtemperature for 38 hrs. and poured onto 400 ml. of ice- 'water coveredwith 50.0 ml. of pentane. The aqueous layer was extracted with two 200ml. portions of pentane and the combined organic solutions were washedwith water (twice) and saturated brine, then dried over anhydrousmagnesium sulfate. The solvent was re moved first by atmosphericdistillation through a Vigreux column and finally under reduced pressureto give 31 g. of a nearly colorless oil which was chromatographed on 160g. of activated magnesium silicate with pentane (500 ml.)..The pentanewas removed as described above to give 20.6 oftrans-l-bromo-3,7-dimethylocta-3,7.-diene as a colorless oil.

b. l 3 17-Dimethyl-bis-2,5-ethylenedioxyoctadeca-trans-13,17-dien-9-yr1e [XV; Y and Y are A is C C, R is CH5].

A solution of 16.72 g. (65.7 mmoles) of 6,9-bis-ethylenedioxy-l-decyne(Example 30 in 130 ml. of dry ether was cooled to C. while 85 ml. (70mmoles) of 0.82M methyllithium in ether was added over 30 min. under anitrogen atmosphere. The resulting white suspension was stirred for min.at 0C. and 30 min. at

.room temperature, then the ether was evaporated under a stream of dry,oxygen-free nitrogen. To the resulting white residue was added 200 ml.of dry tetrahydrofuran to give a nearly colorless solution which wastreated with 14.3 g. (66 mmoles) of trans-l-bromo-3,7-dimethylocta-3,7-diene in 50 ml. of dry tetrahydrofuran over a 60min.period. The resulting milky solution was boiled under reflux in anitrogen atmosphere. An aliquot removed after 64 hrs. indicated thealkylation was about 6O percent complete, but that no dienic bromide wasleft. The mixture was cooled to -l0C. (after 70 hrs.) and treated with27 ml. (22 mmoles) of 0.82M methyllithium in ether and allowed to warmto room temperature. A solution of 4.8 g. (22 mmoles) of the dienicbromide in ml. of dry tetrahydrofuran was then added and the solutionwas stirred under a stream of nitrogen for 1 hr. to remove ether. Thesolution was refluxed for 36 additional hrs., then cooled and pouredonto 400 ml. of ice-water covered with 300 ml. of ether. The aqueouslayer was extracted with two 100 ml. portions of ether and the combinedether solutions were washed with water and brine, then dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 35 g. of an orange oil whichwas further concentrated at0.2

mm. to give g. of an orange distillation residue. This as a colorlessoil.

EXAMPLE 32 l 3,1 7-Dimethyl-bis-2,5-ethylenedioxytrans,transoctadeca-9,l3,l7triene [XV; Y and Y are A is Cl-l=CH, R is CHA solution of 15.50 g. (39.7 mmoles) of 13,17-dimethyl-bis-2,5-ethylenedioxyoctadeca-trans-l 3,1 7- dien-9-yne(Example 3.1 in ml. of dry ether and 600 ml. of ammonia (distilled fromsodium) was treated with 3.6 g. (0.16 g.-atom of sodium and theresulting blue mixture was stirred under reflux in a nitrogen atmospherefor 2 hrs. The reaction was cautiously quenched with solid ammoniumchloride to give a white mixture whichwas allowed to evaporate under astream of nitrogen. The residue was partitioned between 500 ml. of etherand 100 ml. of water and the aqueous layer was extracted with two 100ml. portionsof ether. The combined either solutions were washed withbrine and dried over magnesium sulfate. The solvent was removed underreduced pressure to give 15.54 g. (100 percent yield) ofl3,l7-dimethyl-bis-2,5-ethylenedioxy-trans,trans-octadeca-9,13,17-triene as a nearly colorlessoil.

EXAMPLE 33 l 3 l 7-Dimethyl-2',5-dioxo-trans,trans-octadeca-9,13,17-triene [VII; Y is C=O, Z is H, R- is CH A mixture of 15.4 g.(39.2 mmoles) of 13,17-dimethyl'bis-2,5-ethylenedioxy-trans,trans-octadeca- 9,13,17-triene(Example 32), 528 ml. of methanol, and 132 ml; of 0.1N hydro-chloricacid was degassed and flushed with nitrogen, then stirred under anitrogen atmosphere at 35C. for 6 hrs. The solution was made slighlybasic with saturated sodium bicarbonate solution trum indicated thepresenceof considerable unhydro lyzed ketal (about 15 percent).

A mixture of 10.95 g. of the above distilled material, 500 ml. ofmethanol, and ml. of 0.1N hydrochloric acid was degassed and heatedunder nitrogen for 3 hrs. at 35C. The reaction was worked up asdescribed above to afford a nearly colorless oil which was evaporativelydistilled at l35--,l40C. (5 p.) to give 10.65 g. of l 3 1.7-dimethyl-2,5 -dioxo-trans,trans-octadeca- 9,13,17-triene as a colorless oil,identical with the compound obtained in Example 19.

I claim:

1. A compound of 'the formula wherein R is hydrogen or methyl, Y and Y".are C=O Y is C=O, n is 2, A is CH=CH and Z is carbethoxy.

3. The compound according to claim 1 wherein R is Y is C=O, n is 2, A isCH=CH and Z is hydrogen.

4. The compound according to claim 1 wherein R is methyl, Y and Y areC=O, A is CH=CH and Z is hydrogen.

5. The compound according toclaim 1 wherein R is methyl, Y and Y aremethyl, Y is n is 2, A is C CH and Z is hydrogen.

6. The compound according to claim 1 wherein R is methyl, Y and Y are nis 2, A is CH=CH and Z is hydrogen.

2. The compound according to claim 1 wherein R is methyl, Y'' is
 3. Thecompound according to claim 1 wherein R is methyl, Y'' is
 4. Thecompound according to claim 1 wherein R is methyl, Y'' and Y* are C O, Ais CH CH and Z is hydrogen.
 5. The compound according to claim 1 whereinR is methyl, Y'' and Y* are
 6. The compound according to claim 1 whereinR is methyl, Y'' and Y* are